Ultrathin NiO nanosheets anchored to a nitrogen-doped dodecahedral carbon framework for aqueous potassium-ion hybrid capacitors.

Hierarchical porous structures and well-modulated interfacial interactions are essential for the performance of electrode materials. The energy storage performance can be promoted by regulating the diffusion behavior of the electrolyte and constructing a coupled interaction at heterogeneous interfaces. Herein, we have synthesized ultrathin NiO nanosheets anchored to nitrogen-doped hierarchical porous carbon (NiO/N-HPC) and applied it to construct aqueous potassium ion hybrid capacitors (APIHCs). The abundant and interconnected porous architecture promotes electrolyte penetration/diffusion and shortens the ion transport path, thereby accelerating storage reaction kinetics. The nitrogen-doped carbon support can achieve optimized metal oxides-carbon interaction and enhance the adsorption ability for the electrolyte ions, leading to earning higher storage capacity. Consequently, the prepared NiO/N-HPC exhibits a superior capacitance of 126.4 F g-1 at a current density of 0.5 A g-1, and the as-fabricated NiO/N-HPC//N-HPC APIHC achieves an ultra-high capacitance retention of 91.6% over 8000 cycles at a current density of 2 A g-1. Meanwhile, the APIHC device shows an excellent energy density of 21.95 W h kg-1 and a power density of 9000 W kg-1.

Inducing Directional Charge Delocalization in 3D-Printable Micro-Supercapacitors Based on Strongly Coupled Black Phosphorus and ReS2 Nanocomposites.

The growing interest in so-called interface coupling strategies arises from their potential to enhance the performance of active electrode materials. Nevertheless, designing a robust coupled interface in nanocomposites for stable electrochemical processes remains a challenge. In this study, an epitaxial growth strategy is proposed by synthesizing sulfide rhenium (ReS2) on exfoliated black phosphorus (E-BP) nanosheets, creating an abundance of robust interfacial linkages. Through spectroscopic analysis using X-ray photoelectron spectroscopy and X-ray absorption spectroscopy, the authors investigate the interfacial environment. The well-developed coupled interface and structural stability contribute to the impressive performance of the 3D-printed E-BP@ReS2-based micro-supercapacitor, achieving a specific capacitance of 47.3 mF cm-2 at 0.1 mA cm-2 and demonstrating excellent long-term cyclability (89.2% over 2000 cycles). Furthermore, density functional theory calculations unveil the positive impact of the strongly coupled interface in the E-BP@ReS2 nanocomposite on the adsorption of H+ ions, showcasing a significantly reduced adsorption energy of -2.17 eV. The strong coupling effect facilitates directional charge delocalization at the interface, enhancing the electrochemical performance of electrodes and resulting in the successful construction of advanced micro-supercapacitors.

Discovery of Sulanemadlin (ALRN-6924), the First Cell-Permeating, Stabilized α-Helical Peptide in Clinical Development.

We report the discovery of sulanemadlin (ALRN-6924), the first cell-permeating, stabilized α-helical peptide to enter clinical trials. ALRN-6924 is a "stapled peptide" that mimics the N-terminal domain of the p53 tumor suppressor protein. It binds with high affinity to both MDM2 and MDMX (also known as MDM4), the endogenous inhibitors of p53, to activate p53 signaling in cells having a non-mutant, or wild-type TP53 genotype (TP53-WT). Iterative structure-activity optimization endowed ALRN-6924 with favorable cell permeability, solubility, and pharmacokinetic and safety profiles. Intracellular proteolysis of ALRN-6924 forms a long-acting active metabolite with potent MDM2 and MDMX binding affinity and slow dissociation kinetics. At high doses, ALRN-6924 exhibits on-mechanism anticancer activity in TP53-WT tumor models. At lower doses, ALRN-6924 transiently arrests the cell cycle in healthy tissues to protect them from chemotherapy without protecting the TP53-mutant cancer cells. These results support the continued clinical evaluation of ALRN-6924 as an anticancer and chemoprotection agent.

Element quality indicator: A quality assessment and defect detection method for software requirement specification.

A software requirements specification (SRS) provides a detailed description of the requirements of a software system that is to be developed. The Element Quality Indicator (EQI) is a novel method to detect defects and assess the quality of an SRS. It does not hinge on review guidelines and is based on the SRS element questions extraction method (EQEM). In this study, we optimized the EQI and carried out a systematic and comprehensive experiment to validate and evaluate its effectiveness. The controlled experiment, which included 60 software engineering students, found that 100% of the subjects identified defects in the SRS using EQI. Moreover, the results indicated that the average number of defects detected with EQI was greater than that of the classical review technique - perspective-based reading. Furthermore, the controlled experiment demonstrated that EQI provides a comparatively objective and accurate evaluation of the quality of the SRS and markedly diminishes the bias in understanding software requirements due to the ambiguity of natural language.

Improving the performance of silicon monoxide anodes via tuning a multiple pre-doping system: a first-principles study.

Silicon monoxide is a potentially viable anode material for high-performance lithium-ion batteries (LIBs). However, a low initial coulombic efficiency and large volume expansion limit its commercial application. Pre-lithiation is an efficient solution, but is expensive because of limited "pre-lithiation" sources. In this work, we theoretically investigated a novel multiple pre-doping SiO system (Li-NaMg-SiO). By comparing its lithiation behavior to that of the traditional Li-doping system (Li-SiO), we revealed the different doping effects during lithiation. Similar to the traditional Li-doping system, the insertion of Na and Mg disintegrates the Si-O host matrix to form Na-O and Mg-O bonds and active Si clusters. At the end of lithiation, the O-Li coordination number (CN) tends to saturate at CNO-Li ≈ 5 in Li-Na-SiO, Li-Mg-SiO, and Li-NaMg-SiO systems, while the value of CNO-Li in the Li-SiO system is more than 6, which suggests that there are reorganizations between Li, Na, and Mg in the silicate matrix. Doping sources of both Na and Mg can prevent the active Li ions from being trapped by O-Li bonds and increase the initial coulombic efficiency. From the density of states (DOS), we notice that all the different pre-doping systems have similar electronic structures, and they can be expected to undergo the same lithiation process. Furthermore, the higher ion-conductivity and smaller volume expansion during the lithiation process characterized by root mean square deviation (RMSD) and volume analysis prove the advantages of the binary doping system (Li-NaMg-SiO) for the improvement of cycle stability for Si-based materials. These advantages benefit from the loose and amorphous structures of doping systems during lithiation. Our work highlights the doping effects of multiple sources and the promotion of "inert compounds" on the entire lithiation process, which provide valuable insight for high-performance anode design.

Scalable Synthesis of Pore-Rich Si/C@C Core-Shell-Structured Microspheres for Practical Long-Life Lithium-Ion Battery Anodes.

Silicon/carbon (Si/C) composites have rightfully earned the attention as anode candidates for high-energy-density lithium-ion batteries (LIBs) owing to their advantageous capacity and superior cycling stability, yet their practical application remains a significant challenge. In this study, we report the large-scale synthesis of an intriguing micro/nanostructured pore-rich Si/C microsphere consisting of Si nanoparticles tightly immobilized onto a micron-sized cross-linked C matrix that is coated by a thin C layer (denoted P-Si/C@C) using a low-cost spray-drying approach and a chemical vapor deposition process with inorganic salts as pore-forming agents. The as-obtained P-Si/C@C composite has high porosity that provides sufficient inner voids to alleviate the huge volume expansion of Si. The outer smooth and robust C shells strengthen the stability of the entire structure and the solid-electrolyte interphase. Si nanoparticles embedded in a microsized cross-linked C matrix show excellent electrical conductivity and superior structural stability. By virtue of structural advantages, the as-fabricated P-Si/C@C anode displays a high initial Coulombic efficiency of 89.8%, a high reversible capacity of 1269.6 mAh g-1 at 100 mA g-1, and excellent cycle performance with a capacity of 708.6 mAh g-1 and 87.1% capacity retention after 820 cycles at 1000 mA g-1, outperforming the reported results of Si/C composite anodes. Furthermore, a low electrode swelling of 18.1% at a high areal capacity of 3.8 mAh cm-2 can be obtained. When assembled into a practical 3.2 Ah cylindrical cell, extraordinary long cycling life with a capacity retention of 81.4% even after 1200 cycles at 1C (3.2 A) and excellent rate performance are achieved, indicating significant advantages for long-life power batteries in electric vehicles.

First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models.

BACKGROUND: MDM2/MDMX proteins are frequently elevated in hormone receptor-positive (ER+) breast cancer. We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models. METHODS: Three hundred two cell lines representing multiple tumor types were screened to confirm the role of TP53 status in ALRN-6924 efficacy. ER+ breast cancer cell lines (MCF-7 and ZR-75-1) were used to investigate the antitumor efficacy of ALRN-6924 combination. In vitro cell proliferation, cell cycle, and apoptosis assays were performed. Xenograft tumor volumes were measured, and reverse-phase protein array (RPPA), immunohistochemistry (IHC), and TUNEL assay of tumor tissues were performed to evaluate the in vivo pharmacodynamic effects of ALRN-6924 with paclitaxel. RESULTS: ALRN-6924 was active in wild-type TP53 (WT-TP53) cancer cell lines, but not mutant TP53. On ER+ breast cancer cell lines, it was synergistic in vitro and had enhanced in vivo antitumor activity with both paclitaxel and eribulin. Flow cytometry revealed signs of mitotic crisis in all treatment groups; however, S phase was only decreased in MCF-7 single agent and combinatorial ALRN-6924 arms. RPPA and IHC demonstrated an increase in p21 expression in both combinatorial and single agent ALRN-6924 in vivo treatment groups. Apoptotic assays revealed a significantly enhanced in vivo apoptotic rate in ALRN-6924 combined with paclitaxel treatment arm compared to either single agent. CONCLUSION: The significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.

Positive RT-PCR in urine from an asymptomatic patient with novel coronavirus 2019 infection: a case report.

Introduction: With the emergence of novel coronavirus disease 2019 (COVID-19) in many countries, medical resources currently focus on the treatment of confirmed patients and screening of suspected cases. Asymptomatic patients may be contagious, which makes epidemic control difficult. We describe an asymptomatic patient with a positive real-time polymerase chain reaction (RT-PCR) test in urine.Case report: An asymptomatic girl was identified during the epidemiological investigation of a confirmed COVID-19 patient. When admitted to the hospital on 24 February 2020, she had no clinical manifestations. A throat swab was negative for RT-PCR, but urine was positive. She was given antiviral and symptomatic supportive treatment. On 26 February, a throat swab RT-PCR was positive. RT-PCR in throat swabs and urine were negative on 3 and 5 March, and on 9 and 12 March, throat swabs were still negative. At follow-up on 26 March, she felt well, throat swab RT-PCR was negative, and isolation was lifted.Conclusion: The urine of asymptomatic patients may be contagious. RT-PCR in urine might be a useful supplement in screening when the RT-PCR is negative in throat swabs.

Enhancing the Cell Permeability of Stapled Peptides with a Cyclic Cell-Penetrating Peptide.

Stapled peptides recapitulate the binding affinity and specificity of α-helices in proteins, resist proteolytic degradation, and may provide a novel modality against challenging drug targets such as protein-protein interactions. However, most of the stapled peptides have limited cell permeability or are impermeable to the cell membrane. We show herein that stapled peptides can be rendered highly cell-permeable by conjugating a cyclic cell-penetrating peptide to their N-terminus, C-terminus, or stapling unit. Application of this strategy to two previously reported membrane-impermeable peptidyl inhibitors against the MDM2/p53 and ß-catenin/TCF interactions resulted in the generation of potent proof-of-concept antiproliferative agents against key therapeutic targets.

Structure and conductivity enhanced treble-shelled porous silicon as an anode for high-performance lithium-ion batteries.

Silicon is regarded as the next generation anode material for lithium-ion batteries because of its high specific capacity, low intercalation potential and abundant reserves. However, huge volume changes during the lithiation and delithiation processes and low electrical conductivity obstruct the practical applications of silicon anodes. In this study, a treble-shelled porous silicon (TS-P-Si) structure was synthesized via a three-step approach. The TS-P-Si anode delivered a capacity of 858.94 mA h g-1 and a capacity retention of 87.8% (753.99 mA h g-1) after being subjected to 400 cycles at a current density of 400 mA g-1. The good cycling performance was due to the unique structure of the inner silicon oxide layer, middle silver nano-particle layer and outer carbon layer, leading to a good conductivity and a decreased volume change of this silicon-based anode.

Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models.

T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.

Walnut-structure Si-G/C materials with high coulombic efficiency for long-life lithium ion batteries.

Nano-sized silicon is a potential high energy density anode material for lithium ion batteries. However, the practical use of a nano-Si anode is still challenging due to its low coulombic efficiency, poor scalability and cycling stability. Herein, a Si/graphite/carbon (Si-G/C) composite with a core-shell structure was fabricated by a facile two-step chemical process, stirring-evaporating followed by heat treatment. The composite structure consists of a graphite core, coated first by silicon and then amorphous carbon, which was decomposed by pitch. The as-prepared Si-G/C composite anode demonstrates a first cycle capacity of about 650 mA h g-1, over 90% coulombic efficiency, and high capacity retention of 96.7% after 50 cycles. When paired with a commercial NCA cathode, superior cycling stability with more than 81% capacity retention was achieved for 1200 cycles. These results demonstrate that such a core-shell Si-G/C composite is a promising anode material for high energy Li-ion batteries.

Citrate Suppresses Tumor Growth in Multiple Models through Inhibition of Glycolysis, the Tricarboxylic Acid Cycle and the IGF-1R Pathway.

In this study we have tested the efficacy of citrate therapy in various cancer models. We found that citrate administration inhibited A549 lung cancer growth and additional benefit accrued in combination with cisplatin. Interestingly, citrate regressed Ras-driven lung tumors. Further studies indicated that citrate induced tumor cell differentiation. Additionally, citrate treated tumor samples showed significantly higher infiltrating T-cells and increased blood levels of numerous cytokines. Moreover, we found that citrate inhibited IGF-1R phosphorylation. In vitro studies suggested that citrate treatment inhibited AKT phosphorylation, activated PTEN and increased expression of p-eIF2a. We also found that p-eIF2a was decreased when PTEN was depleted. These data suggest that citrate acts on the IGF-1R-AKT-PTEN-eIF2a pathway. Additionally, metabolic profiling suggested that both glycolysis and the tricarboxylic acid cycle were suppressed in a similar manner in vitro in tumor cells and in vivo but only in tumor tissue. We reproduced many of these observations in an inducible Her2/Neu-driven breast cancer model and in syngeneic pancreatic tumor (Pan02) xenografts. Our data suggests that citrate can inhibit tumor growth in diverse tumor types and via multiple mechanisms. Dietary supplementation with citrate may be beneficial as a cancer therapy.

Vertical Graphene Growth on SiO Microparticles for Stable Lithium Ion Battery Anodes.

Silicon-based materials are considered as strong candidates to next-generation lithium ion battery anodes because of their ultrahigh specific capacities. However, the pulverization and delamination of electrochemical active materials originated from the huge volume expansion (>300%) of silicon during the lithiation process results in rapid capacity fade, especially in high mass loading electrodes. Here we demonstrate that direct chemical vapor deposition (CVD) growth of vertical graphene nanosheets on commercial SiO microparticles can provide a stable conducting network via interconnected vertical graphene encapsulation during lithiation, thus remarkably improving the cycling stability in high mass loading SiO anodes. The vertical graphene encapsulated SiO (d-SiO@vG) anode exhibits a high capacity of 1600 mA h/g and a retention up to 93% after 100 cycles at a high areal mass loading of 1.5 mg/cm2. Furthermore, 5 wt % d-SiO@vG as additives increased the energy density of traditional graphite/NCA 18650 cell by ∼15%. We believe that the results strongly imply the important role of CVD-grown vertical graphene encapsulation in promoting the commercial application of silicon-based anodes.

Propagation Effect of a Virus Outbreak on a Network with Limited Anti-Virus Ability.

This paper describes a new computer virus spreading model which takes into account the possibility of a virus outbreak on a network with limited anti-virus ability. Then, the model is investigated for the existence of equilibria and their stabilities are proved and illustrated. Moreover, it is found that these two factors are not only relative to the threshold value determining whether the virus becomes extinct or not, but that they are also relative to the virus epidemic levels. Theoretical and experimental results indicate that, in some ways, it would be practically possible to eradicate the virus or suppress its prevalence below a suitable level. Consequently, some suggestions are proposed that may help eradicate or suppress virus propagation over a real computer network.

Modelling the effects of selection temperature and mutation on the prisoner's dilemma game on a complete oriented star.

This paper models the prisoner's dilemma game based on pairwise comparison in finite populations on a complete oriented star (COS). First, we derive a linear system on a COS for calculating the corresponding fixation probabilities that imply dependence of the selection temperature and mutation. Then we observe and analyze the effects of two parameters on fixation probability under different population sizes. In particular, it is found through the experimental results that (1) high mutation is more sensitive to the fixation probability than the low one when population size is increasing, while the opposite is the case when the number of cooperators is increasing, and (2) selection temperature demotes the fixation probability.

Design, synthesis and pharmacological evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents.

Two series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 2,4-imidazolinedione/pyrazolone scaffold were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against HT-29, H460, A549, MKN-45, and U87MG cancer cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant cytotoxicity and high selectivity against HT-29, H460 and A549 cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially trifluoromethyl groups at 2-position on the phenyl ring (moiety B) were more effective. In this study, a promising compound 17 (c-Met IC50=2.20nM, a multi-target tyrosine kinase inhibitor) showed the most potent antitumor activities with IC50 values of 0.14µM, 0.18µM, 0.09µM, 0.03µM, and 1.06µM against HT-29, H460, A549, MKN-45, and U87MG cell lines, respectively.

Knockdown of malic enzyme 2 suppresses lung tumor growth, induces differentiation and impacts PI3K/AKT signaling.

Mitochondrial malic enzyme 2 (ME2) catalyzes the oxidative decarboxylation of malate to yield CO2 and pyruvate, with concomitant reduction of dinucleotide cofactor NAD(+) or NADP(+). We find that ME2 is highly expressed in many solid tumors. In the A549 non-small cell lung cancer (NSCLC) cell line, ME2 depletion inhibits cell proliferation and induces cell death and differentiation, accompanied by increased reactive oxygen species (ROS) and NADP(+)/NADPH ratio, a drop in ATP, and increased sensitivity to cisplatin. ME2 knockdown impacts phosphoinositide-dependent protein kinase 1 (PDK1) and phosphatase and tensin homolog (PTEN) expression, leading to AKT inhibition. Depletion of ME2 leads to malate accumulation and pyruvate decrease, and exogenous cell permeable dimethyl-malate (DMM) mimics the ME2 knockdown phenotype. Both ME2 knockdown and DMM treatment reduce A549 cell growth in vivo. Collectively, our data suggest that ME2 is a potential target for cancer therapy.

Targeting lactate dehydrogenase--a inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells.

The lactate dehydrogenase-A (LDH-A) enzyme catalyzes the interconversion of pyruvate and lactate, is upregulated in human cancers, and is associated with aggressive tumor outcomes. Here we use an inducible murine model and demonstrate that inactivation of LDH-A in mouse models of NSCLC driven by oncogenic K-RAS or EGFR leads to decreased tumorigenesis and disease regression in established tumors. We also show that abrogation of LDH-A results in reprogramming of pyruvate metabolism, with decreased lactic fermentation in vitro, in vivo, and ex vivo. This was accompanied by reactivation of mitochondrial function in vitro, but not in vivo or ex vivo. Finally, using a specific small molecule LDH-A inhibitor, we demonstrated that LDH-A is essential for cancer-initiating cell survival and proliferation. Thus, LDH-A can be a viable therapeutic target for NSCLC, including cancer stem cell-dependent drug-resistant tumors.

A silicon nanowire-reduced graphene oxide composite as a high-performance lithium ion battery anode material.

Toward the increasing demands of portable energy storage and electric vehicle applications, silicon has been emerging as a promising anode material for lithium-ion batteries (LIBs) owing to its high specific capacity. However, serious pulverization of bulk silicon during cycling limits its cycle life. Herein, we report a novel hierarchical Si nanowire (Si NW)-reduced graphene oxide (rGO) composite fabricated using a solvothermal method followed by a chemical vapor deposition process. In the composite, the uniform-sized [111]-oriented Si NWs are well dispersed on the rGO surface and in between rGO sheets. The flexible rGO enables us to maintain the structural integrity and to provide a continuous conductive network of the electrode, which results in over 100 cycles serving as an anode in half cells at a high lithium storage capacity of 2300 mA h g(-1). Due to its [111] growth direction and the large contact area with rGO, the Si NWs in the composite show substantially enhanced reaction kinetics compared with other Si NWs or Si particles.